# Tailored Phosphate Leaving Groups Direct Pathway-Dependent Self-Assembly

## TL;DR

This paper shows how different phosphate leaving groups influence the self-assembly and reactivity of aminoacyl phosphate esters in water.

## Contribution

The study reveals that phosphate leaving groups act as tunable design elements to control reactivity and supramolecular assembly.

## Key findings

- Leaving groups guide preorganization into spherical aggregates and influence coassembly with peptides.
- Leaving groups determine supramolecular architectures and mechanical properties of assemblies.
- Soluble phosphates undergo phosphoryl exchange, while self-assembling ones resist it and favor oligomerization.

## Abstract

Phosphate esters
and anhydrides are central to biology, storing
and transferring chemical energy to sustain processes from metabolism
to translation. Among them, acyl phosphates are highly reactive, yet
biology channels their activation chemistry almost exclusively through
aminoacyl adenylates. This conserved design leaves unexplored how
alternative phosphate leaving groups might influence reactivity and
structure. Here we show that aminoacyl phosphate esters with varied
leaving groups (ethyl, phenyl, naphthyl, dodecyl) direct peptide bond
formation and self-assembly through distinct pathways in water. Structural
features of the leaving group guide preorganization into spherical
aggregates before acyl transfer and influence coassembly with peptides
after bond formation, imprinting outcomes that persist beyond activation.
Consequently, the leaving group determines not only peptide yields,
but also the supramolecular architectures and mechanical properties
of assemblies arising from the same peptide sequences. In multicomponent
mixtures, aminoacyl phosphates create recognition microenvironments
in which aromaticity, hydrophobicity, or charge bias electrophile-nucleophile
pairing, thereby transforming them from simple electrophilic reagents
into active design elements capable of driving sequence selectivity.
Moreover, soluble phosphates undergo phosphoryl exchange with orthophosphate,
pyrophosphate, or adenosine monophosphate (AMP) to generate alternative
intermediates that divert reactivity, whereas self-assembling phosphates
resist exchange and favor amino acid oligomerization. These findings
establish the leaving group as a tunable design element that governs
reactivity, directs supramolecular organization and regulates pathway
dynamics, transforming activation from a synthetic step into an active
driver of recognition and assembly.